Journal Article

NOD1CARD Might Be Using Multiple Interfaces for RIP2-Mediated CARD-CARD Interaction: Insights from Molecular Dynamics Simulation

Pradhan, Sukanta Kumar, De, Sachinandan, Maharana, Jitendra

2017

Overview

The nucleotide-binding and oligomerization domain (NOD)-containing protein 1 (NOD1) plays the pivotal role in host-pathogen interface of innate immunity and triggers immune signalling pathways for the maturation and release of pro-inflammatory cytokines. Upon the recognition of iE-DAP, NOD1 self-oligomerizes in an ATP-dependent fashion and interacts with adaptor molecule receptor-interacting protein 2 (RIP2) for the propagation of innate immune signalling and initiation of pro-inflammatory immune responses. This interaction (mediated by NOD1 and RIP2) helps in transmitting the downstream signals for the activation of NF-κB signalling pathway, and has been arbitrated by respective caspase-recruitment domains (CARDs). The so-called CARD-CARD interaction still remained contradictory due to inconsistent results. Henceforth, to understand the mode and the nature of the interaction, structural bioinformatics approaches were employed. MD simulation of modelled 1:1 heterodimeric complexes revealed that the type-Ia interface of NOD1CARD and the type-Ib interface of RIP2CARD might be the suitable interfaces for the said interaction. Moreover, we perceived three dynamically stable heterotrimeric complexes with an NOD1:RIP2 ratio of 1:2 (two numbers) and 2:1. Out of which, in the first trimeric complex, a type-I NOD1-RIP2 heterodimer was found interacting with an RIP2CARD using their type-IIa and IIIa interfaces. However, in the second and third heterotrimer, we observed type-I homodimers of NOD1 and RIP2 CARDs were interacting individually with RIP2CARD and NOD1CARD (in type-II and type-III interface), respectively. Overall, this study provides structural and dynamic insights into the NOD1-RIP2 oligomer formation, which will be crucial in understanding the molecular basis of NOD1-mediated CARD-CARD interaction in higher and lower eukaryotes.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenosine triphosphate / Amino Acid Sequence / Arbitration / Binding Sites / Bioinformatics / Biology and Life Sciences / Caspase / Caspases - metabolism / Computer and Information Sciences / Computer simulation / Cytokines / Dimerization / Eukaryotes / Humans / Hydrogen Bonding / Immune response / Immunity / Inflammation / Innate immunity / Interfaces / Kinases / Ligands / Medicine and Health Sciences / Molecular dynamics / Molecular Dynamics Simulation / NF-κB protein / Nod1 protein / Nod1 Signaling Adaptor Protein - chemistry / Nod1 Signaling Adaptor Protein - metabolism / Oligomerization / Physical Sciences / Proteins / Receptor-Interacting Protein Serine-Threonine Kinase 2 - chemistry / Receptor-Interacting Protein Serine-Threonine Kinase 2 - metabolism / Research and Analysis Methods / Sequence Homology, Amino Acid / Signal transduction / Signaling / Simulation / Static Electricity / Zebrafish